Our long-term objective is to understand the signaling mechanisms and physiological functions of heterotrimeric G proteins and G protein-coupled receptors. G proteins control diverse physiological functions. However, the potential role of G protein signaling in the control of animal aging has not been explored. Recently we have purified an endogenous peptide ligand, designated as shoutao (longevity in Chinese mythology), for the G protein-coupled receptor methuselah which controls lifespan in Drosophila, and that mutations in the gene encoding shoutao extended the lifespan of the flies to the same degree as methuselah mutations. This has provided an extraordinary entry point to investigate the participation of G protein signaling in the central control of lifespan. In this grant application, there are two broad specific aims: I. Study of the shoutao-methuselah system in Drosophila. 1) We will carry out the pharmacological characterization of shoutao and methuselah interaction. 2) We will study the biogenesis of the ligand shoutao. 3) We will examine the tissue distribution of methuselah in Drosophila. 4) We will analyze the stress resistance of shoutao mutant flies. 5) We will investigate the G protein coupling by methuselah in Drosophila cells. II. Study of the shoutao system in mouse. Our long-term goal is to explore the role of G protein signaling in the control of aging in mammals. The shoutao-methuselah system provides an excellent starting point. Therefore, we will: 1) generate knockout mice for shoutao for lifespan studies (the shoutao sequence is conserved in mouse); 2) identify the receptor for shoutao in mouse. This research is directly related to human health. A better understanding of the molecular mechanism of aging will certainly benefit our society. [unreadable] [unreadable]